PI3K信号通路抑制剂研究进展
The Research Progress of PI3K Inhibitors
DOI: 10.12677/HJMCe.2020.83007, PDF,   
作者: 赵咨鉴, 李 驰：辽宁大学药学院，辽宁 沈阳；张明：辽宁省新药研发重点实验室，辽宁 沈阳；王欣*：辽宁大学药学院，辽宁 沈阳；辽宁省新药研发重点实验室，辽宁 沈阳
关键词: PI3K信号通路抑制剂；结构类型；靶点；研究进展；PI3K Signaling Pathway Inhibitors； Structural； Targets； Research Progress
摘要: PI3K信号通路是指PI3K/AKT/mTOR信号通路。在本篇综述中，详细介绍了PI3K信号通路抑制剂的不同分类，PI3K信号通路抑制剂与其活性位点的结合模式，以及PI3K抑制剂的研究进展，揭示了PI3K抑制剂的构效关系和设计思路，以期找到活性高、选择性好、副作用小的药物，为癌症治疗带来希望。PI3K信号通路在人类发育过程中起着重要作用，与多种肿瘤的发生发展密切相关。在PI3K信号通路的不同治疗方法中，小分子PI3K抑制剂在分子靶向抗肿瘤方面具有很大的潜力治疗。目前已知的PI3K抑制剂主要有Copanlisib、Idelalisib Dactolisib、Omipalisib等。
Abstract: PI3K signaling pathway refers to the PI3K/AKT/mTOR signaling pathway. In this review, we briefly summarized the classification of PI3K inhibitors, and the interaction between PI3K inhibitors and PI3K active sites. We also introduced the research progress of PI3K inhibitors in detail, and then revealed the structure-activity relationship and design ideas of PI3K inhibitors in order to find drugs with high activity, good selectivity and small side effects, and bring hope for the cancer ther-apy. PI3K signaling pathway plays an important role in human development and is closely related to the occurrence and development of a variety of tumors. In different treatment methods for PI3K signaling pathway, small molecule PI3K inhibitors have great potential in molecular targeted an-ti-tumor treatment. Currently, the main known PI3K inhibitors are Copanlisib, Idelalisib Dactolisib, Omipalisib, etc.
文章引用：赵咨鉴, 张明, 李驰, 王欣. PI3K信号通路抑制剂研究进展[J]. 药物化学, 2020, 8(3): 51-65. https://doi.org/10.12677/HJMCe.2020.83007

参考文献

[1] Fruman, D.A., Chiu, H., Hopkins, B.D., Bagrodia, S., Cantley, L.C. and Abraham, R.T. (2017) The PI3K Pathway in Human Disease. Cell, 170, 605-635. [Google Scholar] [CrossRef] [PubMed]
[2] Akinleye, A., Avvaru, P., Furqan, M., et al. (2013) Phosphatidylinositol 3-Kinase (PI3K) Inhibitors as Cancer Therapeutics. Journal of Hematolo-gy & Oncology, 6, 88. [Google Scholar] [CrossRef] [PubMed]
[3] PI3K抑制剂类抗肿瘤药Sonolisib[J]. 药学进展, 2013, 37(8): 407-408.
[4] Kong, D. and Yamori, T. (2010) Phosphatidylinositol 3-Kinase Inhibitors: Promising Drug Candidates for Cancer Therapy. Cancer Science, 99, 1734-1740.
[5] 苏畅, 时小燕, 等. 以磷酸肌醇3激酶通路为靶点的抗肿瘤药物[J]. 国际药学研究杂志, 2010, 37(1): 60-63.
[6] 王宇驰, 姚瑜. 抗癌药物磷脂酰肌醇3激酶抑制剂[J]. 国外医药: 抗生素分册, 2008, 29(5): 206-212.
[7] Walker, E.H., Pacold, M.E., Perisic, O., et al. (2000) Structural Determinants of Phosphoinositide 3-Kinase Inhibition by Wortmannin, LY294002, Quercetin, Myricetin, and Staurosporine. Molecular Cell, 6, 909-919. [Google Scholar] [CrossRef] 
[8] Garciaecheverria, C. and Sellers, W.R. (2008) Drug Discov-ery Approaches Targeting the PI3K/Akt Pathway in Cancer. Oncogene, 27, 5511. [Google Scholar] [CrossRef] [PubMed]
[9] Janku, F. (2017) Phosphoinositide 3-Kinase (PI3K) Pathway Inhibitors in Solid Tumors: From Laboratory to Patients. Cancer Treatment Reviews, 59, 93. [Google Scholar] [CrossRef] [PubMed]
[10] 殷勇. 以PI3K为靶点的抗肿瘤化合物的设计、合成及生物活性评价[D]: [博士学位论文]. 南京: 南京大学, 2015.
[11] 吴成军, 赵金龙, 周志旭, 等. 选择性PI3K抑制剂的研究进展[J]. 中南药学, 2014(4): 305-310.
[12] Yu, K., Lucas, J., Zhu, T., et al. (2005) PWT-458, a Novel Pegylat-ed-17-hydroxywortmannin, Inhibits Phosphatidylinositol 3-Kinase Signaling and Suppresses Growth of Solid Tumors. Cancer Biology & Therapy, 4, 538-545. [Google Scholar] [CrossRef] [PubMed]
[13] Garlich, J.R., De, P., Dey, N., et al. (2008) A Vascular Targeted Pan Phosphoinositide 3-Kinase Inhibitor Prodrug, SF1126, with Antitumor and Antiangiogenic Activity. Cancer Research, 68, 206-215. [Google Scholar] [CrossRef] 
[14] Kong, D., Dan, S., Yamazaki, K., et al. (2010) Inhibition Profiles of Phosphatidylinositol 3-Kinase Inhibitors against PI3K Superfamily and Human Cancer Cell Line Panel JFCR39. European Journal of Cancer, 46, 1111-1121. [Google Scholar] [CrossRef] [PubMed]
[15] Urs, H., Sabina, C., Lyndsey, H., et al. (2015) Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel. Molecular Cancer Therapeutics, 14, 48. [Google Scholar] [CrossRef] 
[16] Glauer, J., Pletz, N., Schön, M., et al. (2013) A Novel Se-lective Small-Molecule PI3K Inhibitor Is Effective against Human Multiple Myeloma in Vitro and in Vivo. Blood Cancer Journal, 3, e141. [Google Scholar] [CrossRef] [PubMed]
[17] Serra, V., Markman, B., Scaltriti, M., et al. (2008) NVP-BEZ235, a Dual PI3K/mTOR Inhibitor, Prevents PI3K Signaling and Inhibits the Growth of Cancer Cells with Ac-tivating PI3K Mutations. Cancer Research, 68, 8022-8030. [Google Scholar] [CrossRef] 
[18] 刘珍, 高丰厚. NVP-BEZ235抗肿瘤效应及其机制的研究进展[J]. 肿瘤, 2015, 35(12): 1395-1400.
[19] Schnell, C.R., Stauffer, F., Allegrini, P.R., et al. (2008) Effects of the Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 on the Tumor Vasculature: Implications for Clinical Imaging. Cancer Research, 68, 6598-6607. [Google Scholar] [CrossRef] 
[20] Chakrabarty, A., Sánchez, V., Kuba, M.G., et al. (2012) Feedback Upregulation of HER3 (ErbB3) Expression and Activity Attenuates Antitumor Effect of PI3K Inhibitors. Pro-ceedings of the National Academy of Sciences of the United States of America, 109, 2718-2723. [Google Scholar] [CrossRef] [PubMed]
[21] 吕晓庆. 基于喹啉类及喹喔啉类PI3K/mTOR双重抑制剂的设计、合成与生物活性评价[D]: [博士学位论文]. 杭州: 浙江大学, 2015.
[22] Chang, K.Y., Tsai, S.Y., Wu, C.M., et al. (2011) Novel Phosphoinositide 3-Kinase/mTOR Dual Inhibitor, NVP-BGT226, Displays Potent Growth-Inhibitory Activity against Human Head and Neck Cancer Cells in Vitro and in Vivo. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 17, 7116. [Google Scholar] [CrossRef] 
[23] Knight, S.D., Adams, N.D., Burgess, J.L., et al. (2010) Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin. ACS Medicinal Chemistry Letters, 1, 39-43. [Google Scholar] [CrossRef] [PubMed]
[24] Heffron Timothy, P., et al. (2010) Identification of GNE-477, a Potent and Efficacious Dual PI3K/mTOR Inhibitor. Bioorganic & Medicinal Chemistry Letters, 20, 2408-2411. [Google Scholar] [CrossRef] [PubMed]
[25] 陈颖, 韩进松, 宋云龙, 等. PI3K-mTOR双重小分子抑制剂的研究进展[J]. 药学实践杂志, 2014(5): 332-336.
[26] Zhang, R., Yang, J., Zhou, Y., et al. (2016) N-(2-Hydroxypropyl)methacrylamide Copolymer-Drug Conjugates for Combination Chemotherapy of Acute Myeloid Leukemi. Macromolecular Bioscience, 16, 121-128. [Google Scholar] [CrossRef] [PubMed]
[27] 孙成钰, 周勇, 周红英, 等. 小分子PI3K/mTOR双重抑制剂研究进展[J]. 江西科技师范大学学报, 2016(6): 61-69.
[28] Lee, H., Jung, K.H., Jeong, Y., et al. (2013) HS-173, a Novel Phosphatidylinositol 3-Kinase (PI3K) Inhibitor, Has Anti-Tumor Activity through Promoting Apoptosis and Inhibiting Angiogenesis. Cancer Letters, 328, 152-159. [Google Scholar] [CrossRef] [PubMed]
[29] 张蕾, 邱玉玲, 应莺, 等. PI3K抑制剂ZSTK474对人黑素瘤A375细胞增殖和细胞周期的影响[J]. 国际药学研究杂志, 2017, 44(12): 1118-1124.
[30] 史鑫生, 刘晓蓉, 尤启冬. PI3K抑制剂抗肿瘤临床研究进展[J]. 药学进展, 2017(2): 151-157.
[31] 唐琰, 贡岳松, 徐云根, 等. mTOR抑制剂的研究概况[J]. 有机化学, 2011, 31(7): 1144-1154.
[32] 张亚鲁, 孙铁民. Idelalisib[J]. 中国药物化学杂志, 2015(1): 78.
[33] 王永, 郭壮, 孙晓庆, 等. 特异性PI3K亚型抑制剂抗肿瘤作用研究进展[J]. 中国药物化学杂志, 2016(3): 236-243.
[34] Johnson, A.J. (2010) Phosphatidylinositol 3-Kinase-D Inhibitor CAL-101 Shows Promising Preclinical Activity in Chronic Lymphocytic Leukemia by Antagonizing Intrinsic and Extrinsic Cellular Survival Signals. Blood, 116, 2078. [Google Scholar] [CrossRef] [PubMed]
[35] 刘夏玲. 抗肿瘤干细胞药物研究-mTOR抑制剂的设计与合成[D]: [硕士学位论文]. 武汉: 武汉工程大学, 2017.